Project Summary/Abstract: Septic shock is a common and highly morbid clinical syndrome that affects over 200,000 patients in the United States annually and results in over 40,000 deaths. Kidney failure is a frequent complication of sepsis and septic shock that is associated with worse outcomes. To date, the understanding of kidney injury in sepsis and septic shock has traditionally focused on decreased blood pressure leading to kidney hypoperfusion. Recent studies have challenged this paradigm, however, illustrating that sepsis associated kidney injury often occurs even when perfusion is adequate. These findings suggest that alternative pathophysiologic mechanisms may have a role in sepsis related kidney injury. The mechanisms remain poorly understood and as yet there are no proven interventions aimed at mitigating sepsis-induced kidney injury. Thiamine (vitamin B1), a key cofactor of pyruvate dehydrogenase, is a critical component of oxidative phosphorylation (i.e. aerobic mitochondrial respiration). In the absence of thiamine, mitochondrial metabolism shifts towards anaerobic energy production, which is inefficient and results in lactate production. Thiamine deficiency has also been linked to increased levels of reactive oxygen species. Our research group has previously demonstrated that thiamine deficiency is common in critical illness and inversely associated with lactate levels. We hypothesize that thiamine deficiency during critical illness may occur due to increased metabolic demand which rapidly consumes available thiamine stores. In a randomized trial, our research group has found that the administration of thiamine to thiamine deficient patients with septic shock leads to reduced lactate at 24-hours. In a post-hoc analysis of that study, my work has shown that patients (including both thiamine replete and thiamine deficient patients) who received thiamine had lower creatinine values at 24-hours and were less likely to require kidney replacement therapy (e.g. dialysis). Our research group has also shown improved cellular oxygen consumption in septic patients and cardiac surgery patients who receive thiamine. Given the above, we hypothesize that thiamine attenuates kidney injury during septic shock by supporting aerobic mitochondrial metabolism. To test this hypothesis, we have planned a randomized, double-blind placebo-controlled trial of thiamine to improve in kidney function in patients with septic shock. This award will allow me to further develop as a physician-investigator and to test important hypotheses with potentially significant therapeutic benefits for patients with sepsis and septic shock.